The genome of hepatitis C virus (HCV) encodes two envelope glycoproteins (E1 and E2) which are thought to be responsible for binding of the virus to the cell surface and for mediating membrane fusion which leads to virus penetration and infection. Although some cell lines appear to be permissive for HCV replication, as determined by the detection of HCV genomic RNA, or negative-sense genome replication intermediates by highly sensitive RT-PCR, studies of HCV tropism, and the assessment of protective antibody responses to HCV have been hampered by the lack of a conventional cell culture system which supports multi-cycle HCV replication. One of the ways to overcome this limitation is to develop surrogate virus systems in which the HCV E1 and E2 envelope proteins are incorporated into virions and displayed on the virion surface, but that utilize the replication machinery of a heterologous virus. One such system employs recombinant vesicular stomatitis viruses (VSVs), which have been shown previous to express and incorporate a variety of foreign glycoproteins in the viral envelope. VSV replicates well in many different types of animal cells and it has been used extensively as a tool to dissect the entry mechanism of enveloped RNA viruses. Therefore, the development of recombinant VSVs encoding the envelope proteins of HCV provides a novel approach to examine the mechanism of HCV entry. In this proposal we describe how will use a series of recombinant VSVs encoding HCV envelope proteins to study the early events in HCV infection. The goals of this research are to: 1) develop a surrogate HCV system utilizing recombinant vesicular stomatitis viruses (rVSVs) encoding chimeric hepatitis C virus (HCV) E1 and E2 proteins; 2) examine the cell entry properties of rVSV/HCV; 3) determine if there is a correlation between appearance of E1 and E2 variants during quasi- species evolution and neutralizing antibody in the sera of African- American patients that do not respond to interferon therapy and in a matched group of Caucasian non-responders, compared to patients that do respond to therapy and, 4) identify compounds from a library of small molecules that inhibit rVSV/HCV infection.